HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: Analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

Abstract

HER2-overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK/AKT-pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1,914 patients in the QUASAR stage II-III trial and 1,342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data was obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR. 29/1,342 (2.2%) stage IV and 25/1,914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2-amplification by FISH. 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF-wildtype (WT) status in all stages: in 5.2% WT versus 1.0% mutated tumours (p<0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p=0.01) respectively. HER2 was not associated with OS or PFS. In stage II-III, there was no significant correlation between HER2-overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF-WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial.

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Item Type:	Article
Authors/Creators:	Richman, SD https://orcid.org/0000-0003-3993-5041 Southward, K Chambers, P https://orcid.org/0000-0002-0926-717X Cross, D Barrett, J https://orcid.org/0000-0002-1720-7724 Hemmings, G Taylor, M Wood, H https://orcid.org/0000-0003-3009-5904 Hutchins, G Foster, JM Oumie, A Spink, KG Brown, SR Jones, M Kerr, D Handley, K Gray, R Seymour, M https://orcid.org/0000-0002-2441-9629 Quirke, P https://orcid.org/0000-0002-3597-5444
Copyright, Publisher and Additional Information:	© 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
Keywords:	HER2;Colorectal cancer;amplification;overexpression;copy number variation
Dates:	Published: March 2016 Published (online): 22 December 2015 Accepted: 12 December 2015
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > Medicine & Health Faculty Office (Leeds) > Leeds Inst for Data Analytics (LIDA) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Pathology & Tumour Biology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Clinical Trials Research (LICTR) (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	27 Jan 2016 12:11
Last Modified:	19 Jun 2020 14:46
Published Version:	http://dx.doi.org/10.1002/path.4679
Status:	Published
Publisher:	Wiley
Identification Number:	10.1002/path.4679
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:94317

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HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: Analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

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